chr17-65557819-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004655.4(AXIN2):​c.802G>C​(p.Asp268His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D268N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

AXIN2
NM_004655.4 missense

Scores

1
5
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.45

Publications

2 publications found
Variant links:
Genes affected
AXIN2 (HGNC:904): (axin 2) The Axin-related protein, Axin2, presumably plays an important role in the regulation of the stability of beta-catenin in the Wnt signaling pathway, like its rodent homologs, mouse conductin/rat axil. In mouse, conductin organizes a multiprotein complex of APC (adenomatous polyposis of the colon), beta-catenin, glycogen synthase kinase 3-beta, and conductin, which leads to the degradation of beta-catenin. Apparently, the deregulation of beta-catenin is an important event in the genesis of a number of malignancies. The AXIN2 gene has been mapped to 17q23-q24, a region that shows frequent loss of heterozygosity in breast cancer, neuroblastoma, and other tumors. Mutations in this gene have been associated with colorectal cancer with defective mismatch repair. [provided by RefSeq, Jul 2008]
AXIN2 Gene-Disease associations (from GenCC):
  • oligodontia-cancer predisposition syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
  • tooth agenesis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • craniosynostosis
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2245011).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AXIN2NM_004655.4 linkc.802G>C p.Asp268His missense_variant Exon 2 of 11 ENST00000307078.10 NP_004646.3 Q9Y2T1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AXIN2ENST00000307078.10 linkc.802G>C p.Asp268His missense_variant Exon 2 of 11 1 NM_004655.4 ENSP00000302625.5 Q9Y2T1
ENSG00000266076ENST00000577662.1 linkn.*978G>C non_coding_transcript_exon_variant Exon 4 of 7 2 ENSP00000462418.1 J3KSC3
ENSG00000266076ENST00000577662.1 linkn.*978G>C 3_prime_UTR_variant Exon 4 of 7 2 ENSP00000462418.1 J3KSC3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Oligodontia-cancer predisposition syndrome Uncertain:1
Sep 06, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 1400290). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 268 of the AXIN2 protein (p.Asp268His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with AXIN2-related conditions. -

Hereditary cancer-predisposing syndrome Uncertain:1
Dec 15, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.D268H variant (also known as c.802G>C), located in coding exon 1 of the AXIN2 gene, results from a G to C substitution at nucleotide position 802. The aspartic acid at codon 268 is replaced by histidine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.0086
T
BayesDel_noAF
Benign
-0.25
CADD
Uncertain
24
DANN
Benign
0.83
DEOGEN2
Benign
0.23
.;T;T;T
Eigen
Benign
-0.17
Eigen_PC
Benign
-0.053
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
.;D;.;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.22
T;T;T;T
MetaSVM
Benign
-0.28
T
PhyloP100
7.5
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-0.73
N;.;N;.
REVEL
Uncertain
0.33
Sift
Uncertain
0.0090
D;.;D;.
Sift4G
Uncertain
0.011
D;D;D;.
Polyphen
0.55
.;P;P;.
Vest4
0.13
MutPred
0.21
Gain of MoRF binding (P = 0.0401);Gain of MoRF binding (P = 0.0401);Gain of MoRF binding (P = 0.0401);Gain of MoRF binding (P = 0.0401);
MVP
0.68
MPC
0.33
ClinPred
0.53
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.40
Mutation Taster
=67/33
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs745659837; hg19: chr17-63553937; API